Preparation of 4-amino-1-naphthol ethers

ABSTRACT

The present invention describes a process for preparing 4-amino-1-naphthol ethers which is characterized in that naphthol ethers are first prepared from 1-naphthols, the former are then converted to the corresponding 4-acetamino-1-naphthol ethers and then the acyl group is cleaved off, and further describes 4-acetamino-1-naphthol ethers obtained thereby.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a process for preparing4-amino-1-naphthol ethers and novel intermediates.

[0003] 2. Brief Description of the Prior Art

[0004] 4-Amino-1-naphthol ethers are valuable intermediates in preparingactive pharmaceutical ingredients (see, for example, WO 00/43384; B.Bachman, J. Wetzel, J. Org. Chem., 11,1946, p. 454-462; R. Herbst, P.Johnson, J. Org. Chem., 17, 1952, p. 693-697). The synthetic routedisclosed, for example, by WO 00/43384 starts from 4-amino-1-naphtholhydrochloride and comprises the conversion of the amine to a protectedderivative, the alkylation of the hydroxy group and then the cleavage ofthe protecting group. This process has the disadvantage that both thereactant and the protecting group reagents used are very expensive andthe conversion to the desired 4-amino-1-naphthol ethers still requiresthree steps. The synthesis of 4-amino-1-methoxynaphtalene according toB. Bachman, J. Wetzel, J. Org. Chem., 11,1946, p. 454-462 is similar andaccordingly has the same disadvantages.

[0005] There is accordingly a need to develop an efficient processwhich, starting from inexpensive 1-naphthols, facilitates thepreparation of 4-amino-1-naphthol ethers in a few steps.

SUMMARY OF THE INVENTION

[0006] A process for preparing 4-amino-1-naphthol ethers has now beenfound that is characterized in that

[0007] a) substituted or unsubstituted 1-naphthols are reacted withreactive alkyl compounds optionally in the presence of a base, to give1-naphthol ethers,

[0008] b) the 1-naphthol ethers are then converted to the corresponding4-acylamino-1-naphthol ethers using hydroxylammonium salts andcarboxylic acids and

[0009] c) these 4-acylamino-1-naphthol ethers are converted to the free4-amino-1-naphthol ethers or analogous ammonium salts by acidic or basicacyl group cleavage.

DETAILED DESCRIPTION OF THE INVENTION

[0010] Preference is given to using the substituted or unsubstituted1-naphthols of the general formula (I) for step a) of the processaccording to the invention

[0011] where

[0012] R² is hydrogen, halogen or C₁-C₄-alkyl and

[0013] R³ is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and

[0014] n is zero, one, two, three or four and

[0015] R⁴ are each independently halogen, nitro, cyano, protectedformyl, C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl,C₁-C₈-haloalkyl or C₆-C₁₀-aryl or substituents of the general formula(II),

D-E-F  (II)

[0016] where, independently,

[0017] D is absent or is a C₁-C8-alkylene radical and

[0018] E is a carbonyl group or sulphonyl group and

[0019] F is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷,

[0020] where

[0021] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or

[0022] NR⁶R⁷ together is a 5- to 8-membered heterocycle.

[0023] Alkyl or alkylene in the context mentioned are each independentlya straight-chain, cyclic, branched or unbranched alkyl or alkyleneradical. The same applies to the alkyl moiety of an arylalkyl radical.

[0024] Examples of C₁-C₄-alkyl radicals include methyl, ethyl, n-propyl,isopropyl and n-butyl, and for C₁-C₈-alkyl radicals also n-pentyl,n-hexyl, cyclohexyl, n-heptyl, n-octyl and isooctyl.

[0025] Examples of C₁-C₈-alkylene radicals include methylene,1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, 1,4-butyleneand 1,2-cyclohexylene.

[0026] Examples of C₇-C₁₂-arylalkyl radicals include benzyl andp-methylbenzyl.

[0027] Examples of C₁-C₄-alkoxy radicals include methoxy, ethoxy,n-propoxy, isopropoxy and n-butoxy.

[0028] The term aryl refers both to carbocyclic and heteroaromaticradicals in which none, one, two or three skeletal carbon atoms percycle, but at least one skeletal carbon atom in the entire radical, issubstituted by heteroatoms selected from the group consisting ofnitrogen, sulphur and oxygen. The carbocyclic aromatic radicals orheteroaromatic radicals may further be substituted by up to fiveidentical or different substituents per cycle selected from the groupconsisting of bromine, chlorine, fluorine, nitro, cyano, free orprotected formyl, C₁-C₈-alkyl, C₁-C₈-hydroxyalkyl and radicals asdefined for the general formula (II).

[0029] Carbocyclic, aromatic radicals or heteroaromatic radicals may be,for example, substituted or unsubstituted phenyl, pyridyl, imidazolyl orpyrazolyl.

[0030] The same applies to the aryl moiety of an arylalkyl radical.

[0031] Halogen in the context mentioned is fluorine, chlorine, bromineor iodine.

[0032] Haloalkyl in the context mentioned is independently astraight-chain, cyclic, branched or unbranched alkyl radical which issubstituted by one, more than one or completely by halogen atomsselected independently from the group consisting of fluorine, chlorineand bromine.

[0033] Examples of C₁-C₈-haloalkyl radicals include trifluoromethyl,pentafluoroethyl, 2,2,2-trifluoroethyl, trichloromethyl and2-chloroethyl.

[0034] Each hydroxyalkyl in the context mentioned is independently astraight-chain, cyclic, branched or unbranched alkyl radical which issubstituted by one or more hydroxyl groups in such a way that eachcarbon atom of the radical bears not more than one oxygen, sulphur ornitrogen atom.

[0035] Examples of C₁-C₈-hydroxyalkyl radicals include hydroxymethyl and2-hydroxyethyl.

[0036] Protected formyl is a formyl radical which is protected byconversion to aminal, acetal or a mixed aminalacetal, and the aminals,acetals and mixed aminalacetals may be acyclic or cyclic.

[0037] A 5- to 8-membered heterocycle is a heterocycle which, as well asa nitrogen, also contains up to 3 further heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulphur.

[0038] Examples of such heterocycles include unsubstituted orsubstituted pyrrolidines, piperidines or morpholines.

[0039] Particular preference is given to using substituted orunsubstituted 1-naphthols of the general formula (I) in step a) of theprocess according to the invention where

[0040] R² is hydrogen and

[0041] R³ is hydrogen and

[0042] n is zero, one or two and

[0043] R⁴ are each independently halogen, nitro, cyano, C₁-C₈-alkyl,C₁-C8-haloalkyl or substituents of the general formula (III),

[0044] where, independently,

[0045] D is absent and

[0046] E is a carbonyl group or sulphonyl group and

[0047] F is R⁶, OR⁶, NH₂, NHR⁶ or NR⁶R⁷ and where

[0048] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₄-alkyl.

[0049] Very particular preference is given to using 1-naphthol in stepa).

[0050] The substituted or unsubstituted 1-naphthols are reacted in stepa) with reactive alkyl compounds to give 1-naphthol ethers, optionallyin the presence of a base.

[0051] Examples of reactive alkyl compounds include compounds of thegeneral formula (IIIa) or (IIIb),

R¹—Y   (IIIa)

(R¹—O)₂SO₂   (IIIb)

[0052] where, for example,

[0053] R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl, C₇-C₁₃-arylalkyl orsubstituents of the general formula (IV),

A-B   (IV)

[0054] where

[0055] A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and

[0056] B is NR⁶R⁷, SR⁶ or OR⁶

[0057] where

[0058] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or

[0059] NR⁶R⁷ together is a 5- to 8-membered heterocycle and

[0060] Y is chlorine, bromine, iodine or sulphonate.

[0061] Particular preference is given to using activated alkyl compoundsof the general formula (IIIa) where

[0062] R¹ is a substituent of the general formula (IV) where

[0063] A is C₂-C₄-alkylene or C₂-C₄-haloalkylene and

[0064] B is NR⁶R⁷or OR⁶and

[0065] where

[0066] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₄-alkyl or

[0067] NR⁶R⁷ together is a 5- or 6-membered heterocycle and

[0068] Y is chlorine, bromine, iodine, methanesulphonate, tosylate ortrifluoromethanesulphonate.

[0069] Very particular preference is given to using activated alkylcompounds of the general formula (IIIa) where

[0070] R¹ is a substituent of the general formula (IV) where

[0071] A is 1,2-ethylene and

[0072] B is NR⁶R⁷ or OR⁶,

[0073] where

[0074] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₄-alkyl or

[0075] NR⁶R⁷ together is pyrrolidinyl, piperidinyl or morpholinyl and

[0076] Y is chlorine, bromine or trifluoromethanesulphonate.

[0077] Greatest preference is given to N-(2-chloroethyl)morpholine,N-(2-bromoethyl)morpholine, N-(2-methanesulphonylethyl)morpholine, andeven greater preference to N-(2-chloroethyl)morpholine.

[0078] Preference is given to using the compounds of the generalformulae (IIIa) and (IIIb) when they contain an amine nitrogen in theform of their ammonium salts.

[0079] For example, N-(2-chloroethyl)morpholine is preferably used inthe form of a hydrochloride.

[0080] The compounds of the general formulae (IIIa) or (IIIb) may beused, for example, in a molar ratio of from 0.8 to 2.0, based on thesubstituted or unsubstituted 1-naphthol used, and preference is given toa ratio of from 0.9 to 1.5, even greater preference to a ratio of from1.0 to 1.4.

[0081] The conversion of substituted or unsubstituted 1-naphthols to the1-naphthol ethers may be carried out, for example, in the presence ofbase in a suitable solvent at a suitable temperature.

[0082] Examples of useful bases include hydroxides, alkoxides, hydrides,amides, carbonates and hydrogen carbonates of alkali metals or alkalineearth metals or amines.

[0083] Preference is given to the hydroxides or carbonates of the alkalimetals, more preference to sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate. Very particular preference is given tosodium hydroxide.

[0084] Preference is given to using alkali metal hydroxides in the formof an aqueous solution having a base content of from 30 to 70% byweight, greater preference to a solution of from 30 to 70% by weight ofsodium hydroxide in water.

[0085] The base quantity may be, for example, from 0.8 to 5.0equivalents, based on the substituted or unsubstituted 1-naphthol used,preference is given to from 0.9 to 1.5 equivalents, even greaterpreference to from 0.9 to 1.2 equivalents.

[0086] When, for example, compounds of the general formulae (IIIa) or(IIIb) having amine nitrogen are used in the form of their ammoniumsalts, the base quantity has to be increased by a corresponding molarquantity.

[0087] Examples of useful solvents for step a) of the process accordingto the invention include aliphatic or aromatic hydrocarbons, such as ,toluene, xylene or hexane, chlorinated hydrocarbons, such as ,chlorobenzene or methylene chloride, ethers, such as , tetrahydrofuranor diethyl ether, alcohols, such as , methanol, ethanol or isopropanol,esters, such as ethyl acetate, or polar aprotic solvents, such as ,dimethylformamide or dimethyl sulphoxide, or mixtures of suchsolvents.Preference is given to carrying out the reaction in an alcohol.

[0088] A very particularly preferred solvent for step a) is ethanol.

[0089] The temperature for step a) may, for example, be from 0 to 120°C., preferably from 20 to 80° C., more preferably from 40 to 80° C.

[0090] The pressure during the reaction is preferably ambient pressure.

[0091] In a preferred embodiment of step a), for example, thesubstituted or unsubstituted 1-naphthol and the reactive alkyl compound,for example N-(2-chloroethyl)morpholinyl hydrochloride, is initiallycharged in ethanol and sodium hydroxide is added as a 30-70% aqueoussolution at from 40 to 60° C.

[0092] In the manner according to the invention, 1-naphthol ethers, forexample, of the general formula (V) are obtained,

[0093] where

[0094] R¹, R², R³, R⁴ and n are as defined above with the areas ofpreference mentioned.

[0095] The acylamination of the electron-rich aromatics, for example a1-methoxynaphtalene, is disclosed by T. Cablewski et al., J. Org. Chem.,1994, 59, p. 5814-5817, but the process described there is only slightlyregioselective.

[0096] According to the invention, step b), the conversion of the1-naphthol ethers to 4-acylamino-1-naphthol ethers may, for example, becarried out in such a way, that the 1-naphthol ethers are reacted with ahydroxylammonium salt and a carboxylic acid in the presence ofpolyphosphoric acid.

[0097] For the purposes of the present invention, polyphosphoric acidrefers to such polyphosphoric acids which have a content of over 100%,based on orthophosphoric acid.

[0098] Preference is given to a content of from 100% to 300%, morepreferably from 100% to 150%. Very particular preference is given tocommercial polyphosphoric acid having a content of 116%, based onorthophosphoric acid.

[0099] The quantity of the polyphosphoric acid used may, for example, befrom 5 to 12 times, preferably from 5 to 8 times, the molar quantity ofthe unsubstituted or substituted 1-naphthol ether. The molar quantity ofpolyphosphoric acid reported is based on the content of orthophosphoricacid.

[0100] Examples of useful hydroxylammonium salts include hydroxylaminehydrochloride, hydroxylamine hydrogensulphate and hydroxylaminedihydrogenphosphate.Preference is given to hydroxylamine hydrochloride.

[0101] Examples of useful carboxylic acids include those of the generalformula (VI)

[0102] where

[0103] R⁵ is C₁-C₆-alkyl or C₁-C₄-haloalkyl or anhydrides thereof.

[0104] Preference is given to acetic acid, trifluoroacetic acid,propionic acid and anhydrides thereof, and particular preference isgiven to acetic acid, propionic acid and trifluoroacetic acid. Evengreater preference is given to acetic acid.

[0105] The quantity of the carboxylic acid of the general formula (VI)used may, for example, be from 0.8 to 20 times the molar quantity of theunsubstituted or substituted 1-naphthol ether used, preferably from 1.0to 3.0 times, more preferably from 1.2 to 1.5 times.

[0106] The temperature during the reaction may, for example, be from 50to 130° C., preferably from 70 to 120° C.

[0107] The overall reaction duration may, for example, be from 1 to 48hours, preferably from 2 to 10 hours, more preferably from 5 to 8 hours.

[0108] In a preferred embodiment of step b), carboxylic acid,hydroxylammonium salt and polyphosphoric acid are initially charged andthe 1-naphthol ether is metered in at a temperature of from 70 to 90° C.over a period of from 0.5 to 8 hours, preferably from 1 to 5 hours andmore preferably from 2 to 4 hours, and then heated at 100-120° C. for aperiod of from 1 to 10 hours, preferably from 1 to 4 hours.

[0109] Preference is given to effecting the workup in such a way thatthe reaction mixture is brought into contact with ice and, optionallyafter addition of water, the pH is adjusted using a base, preferablysodium hydroxide, to from 9 to 10. Preference is given to holding thetemperature below 40° C., more preferably at or below 25° C.

[0110] In the manner according to the invention, for example,4-acylamino-1-naphthol ethers of the general formula (VIIa) areobtained,

[0111] where

[0112] R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl, C₇-C₁₃-arylalkyl orsubstituents of the general formula (IV),

A-B  (IV)

[0113] where

[0114] A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and

[0115] B is NR⁶R⁷, SR⁶ or OR⁶,

[0116] where

[0117] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C8-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or

[0118] NR⁶R⁷ together is a 5- to 8-membered heterocycle and

[0119] R² is hydrogen, halogen or C₁-C₄-alkyl and

[0120] R³ is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and

[0121] n is zero, one, two, three or four and

[0122] R⁴ are each independently halogen, nitro, cyano, protectedformyl, C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl,C₁-C₈-haloalkyl or C₆-C₁₀-aryl or substituents of the general formula(II)

D-E-F  (II)

[0123] where, independently,

[0124] D is absent or is a C₁-C₈-alkylene radical and

[0125] E is a carbonyl group or sulphonyl group and

[0126] F is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷,

[0127] and where

[0128] R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or

[0129] NR⁶R⁷ together is a 5- to 8-membered heterocycle and

[0130] R⁵ is C₁-C₆-alkyl or C₁-C₄-haloalkyl.

[0131] The compounds of the general formula (VIIa) are likewise part ofthe subject-matter of the invention.Examples of individual compoundsinclude 4-(2-([1]-naphthyloxy-[4]-acetamino)ethyl)morpholine,4-(2-([1]-naphthyloxy-[4]-propionylamino)ethyl)morpholine and4-(2-([1]-naphthyloxy-[4]-trifluoroacetamino)ethyl)morpholine.

[0132] The compounds of the general formula (VIIa) may either be storedor reacted further.Preference is given to further reactions. If thecompounds of the general formula (VIIa) are to be stored and R¹ alsocontains amine nitrogen, the compounds can also be converted to theanalogous ammonium compounds.For example,4-(2-([1]-naphthyloxy-[4]-acetamino)ethyl)morpholine,4-(2-([1]-naphthyloxy-[4]-propionylamino)ethyl)morpholine and4-(2-([1]-naphthyloxy-[4]-trifluoro-acetamino)ethyl)morpholine can beconverted to the corresponding morpholinium salts by reacting thecompounds, optionally in a solvent, with an equivalent of an acid, H-An.

[0133] The compounds of the general formula (VIIb) accordingly also formpart of the subject-matter of the invention

[0134] where

[0135] R⁵ is a C₁-C₆-alkyl or C₁-C₄-haloalkyl radical

[0136] and An⁻

[0137] is the anion of an acid.

[0138] Preferred H-An acids include mineral acids, for example,sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid ortetrafluoroboric acid, hydrogen halides, for example, hydrogen chlorideor hydrogen bromide, carboxylic acids such as those of the generalformula (VI), where R⁵ is as defined above , or sulphonic acids, forexample methanesulphonic acid. The anions, An derive correspondinglyfrom the H-An acids.

[0139] The 4-acylamino-1-naphthol ethers may be converted to thecorresponding 4-amino-1-naphthol ethers according to step c). This stepmay be effected in a manner similar to the literature (for example, B.Bachman, J. Wetzel, J. Org. Chem., 11, 1946, p. 454-462), for example,by acidic or alkaline acyl group cleavage, and preference is given tohydrolysis used in an acid, which converts the 4-amino-1-naphthol ethersto the form of ammonium salts. When R¹ radicals which contain aminenitrogen are used, the 4-amino-1-naphthol ether occur in the form of thediammonium salts.

[0140] Examples of useful acids include those which have a pKa of 2 orless. Examples thereof include hydrogen halides such as hydrogenchloride, hydrogen bromide or hydrogen iodide, mineral acids, forexample, hydrochloric acid, hydrobromic acid, sulphuric and/orphosphoric acid, or organic sulphonic acids, such as methanesulphonicacid, or mixtures of such acids.

[0141] Preference is given to hydrochloric acid and sulphuric acid, veryparticular preference to concentrated hydrochloric acid.

[0142] In the manner according to the invention, step c) gives4-amino-1-naphthol ethers of the general formula (VIIIa) or the ammoniumsalts thereof of the general formula (VIIIb)

[0143] where

[0144] R¹, R², R³, R⁴ and n are as defined for formula (VIIa) and

[0145] X is the anion of an acid.

[0146] If the R¹ radical contains amine nitrogen, the formula (VIIIb)also includes the ammonium salts thereof.

[0147] An example of an individual compound is4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholine dihydrochloride.

[0148] The compounds of the general formulae (VIIa), (VIIb), (VIIIa) and(VIIIb) are suitable in particular for use in a process for preparingpharmaceuticals.

[0149] The process according to the invention is in particular notablein that it uses the inexpensive 1-naphthols as starting substances andleads selectively in a few steps to the desired 4-amino-1-naphtholethers or ammonium salts thereof in high yields.

[0150] The invention is further illustrated but is not intended to belimited by the following examples in which all parts and percentages areby weight unless otherwise specified.

EXAMPLES Example 1

[0151] Preparation of 4-(2-([1]-naphthyloxy)ethyl)morpholine

[0152] 441 g of 1-naphthol and 648 g of N-(2-chloroethyl)morpholinehydrochloride are initially charged in 2680 ml of ethanol at 50° C. 554g of 50% aqueous sodium hydroxide are added dropwise within 3 h.Stirring is then continued at 50° C. for 3 h and then for 1 h underreflux.

[0153] The salt formed is filtered off and washed with ethanol. Thecombined filtrates are concentrated on a rotary evaporator “to dryness”at 80° C. in a bath and 10 mbar. The cooled residue is dissolved in 1200ml of diethyl ether and extracted first with 180 ml of water, then twicewith 450 ml of 5% aqueous sodium hydroxide each time and finally twicewith 150 ml of water each time. The ether phase is dried over sodiumsulphate and concentrated at 60° C. and 10 mbar to dryness.

[0154] Yield: 741 g 4-(2-([1]-naphthyloxy)ethyl)morpholine in a purityof 97.7% (GC). This corresponds to 93.8% of theory, based on 1-naphthol.

Example 2

[0155] Preparation of4-(2-([1]-naphthyloxy-[4]-acetamido)ethyl)morpholine

[0156] 376 g of glacial acid and 224 g of hydroxylammonium chloride areinitially charged in 2090 g of polyphosphoric acid at 80° C. in astirred flask. 830 g of 4-(2-([1]-naphthyloxy)ethyl)morpholine aremetered in with good stirring within 3 h. During the metering in, thetemperature should not exceed 90° C. Stirring is then continued first at80-90° C. for 1 h and then at 115° C. for a further 3 h.

[0157] The reaction mixture is allowed to cool to 80° C. and stirredwith 1800 g of ice. The temperature is allowed to fall to 30-35° C.After addition of 9.75 l of water, precipitation is effected using 50%aqueous sodium hydroxide (2005 g) to a pH of 4-5. During theprecipitation, the temperature should not exceed 25° C. Stirring iscontinued for 30 min and the precipitate is then filtered off. Theresulting filtercake is washed with a little water.

[0158] The filtercake is suspended in 10 l of water and is dissolvedwith heating to 90° C. The solution is clarified using activated carbon.530 g of 50% aqueous sodium hydroxide is added with stirring in 1 huntil a pH of 10 is obtained. The resulting crystal suspension isfiltered off at 50° C. and the resulting filtercake washed to neutralitywith a lot of water. The filtercake is then dried in a vacuum dryingcabinet.

[0159] Weight: 846 g of4-(2-([1]-naphthyloxy-[4]-acetamido)ethyl)morpholine in a purity of99.3% (HPLC). This corresponds to 85.1% of theory, reckoned on4-(2-([1]-naphthyloxy)ethyl)morpholine

[0160] Elemental analysis: Theoretical: C = 68.77% H = 7.05% N = 8.91%Found: C = 68.65% H = 6.9% N = 8.8%

Example 3

[0161] 4-(2-([1]-Naphthyloxy-[4]-amino)ethyl)morpholine Dihydrochloride

[0162] 846 g of 4-[2-([1]-naphthyloxy-[4]-acetamido)ethyl]morpholine aresuspended in 1340 ml of water and stirred with 2470 g of 37%hydrochloric acid. Hydrolysis is then effected at 95° C. for 5 h. At theend of the reaction time, 1600 g of isopropanol are added and thesuspension is cooled with stirring. The resulting crystals are filteredoff and washed with 4530 g of isopropanol until the filtrate issubstantially colourless. Recrystallization is then effected fromethanol and the product dried in a vacuum drying cabinet.

[0163] Yield: 839 g of 4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholinedihydrochloride.

Example 4

[0164] Preparation of the Free4-(2-([1]-naphthyloxy-[4]-amino)ethyl)morpholine

[0165] 839 g of the dihydrochloride from Example 3 are dissolved in 5600ml of water. In a beaker, 450 ml of water are adjusted to pH 12 using50% aqueous sodium hydroxide. After seed crystals are created in theaqueous sodium hydroxide initial charge, 50% aqueous sodium hydroxide issimultaneously added dropwise to the remaining solution in such a waythat the pH of 10-12 is maintained. 390 g of 50% aqueous sodiumhydroxide are used. The resulting crystals are filtered off and washedwith 3300 ml of water until the filtrate has a pH of 8. The filtercakeis then dried in the vacuum drying cabinet.

[0166] The yield of free amine is virtually quantitative (620 g) in apurity of 99.4% (HPLC).

[0167] Although the invention has been described in detail in theforegoing for the purpose of illustration, it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those skilled in the art without departing from the spiritand scope of the invention except as it may be limited by the claims.

What is claimed is:
 1. Process for preparing 4-amino-1-naphthol ethers,comprising reacting: a) substituted or unsubstituted 1-naphthols withreactive alkyl compounds to give 1-naphthol ethers, b) converting the1-naphthol ethers to the corresponding 4-acylamino-1-naphthol ethersusing hydroxyl ammonium salts and carboxylic acids and c) converting the4-acylamino-1-naphthol ethers to the free 4-amino-1-naphthol ethers oranalogous ammonium salts by acidic or basic acyl group cleavage. 2.Process according to claim 1, wherein the substituted or unsubstituted1-naphthols have the general formula (I)

where R² is hydrogen, halogen or C₁-C₄-alkyl and R³ is hydrogen,halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and n is zero, one, two, three orfour and R⁴ are each independently halogen, nitro, cyano, protectedformyl, C₁-C₈-alkyl, C₇-C₁₀-arylalkyl, C₁-C₈-hydroxyalkyl,C₁-C₈-haloalkyl or C₆-C₁₀-aryl or substituents of the general formula(II), D-E-F  (II) where, independently, D is absent or is aC₁-C₈-alkylene radical and E is a carbonyl group or sulphonyl group andF is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷, and where R⁶ and R⁷ are eachindependently substituted or unsubstituted C₁-C₈-alkyl, C₁-C₈-haloalkyl,C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or NR⁶R⁷together is a 5- to 8-memberedheterocycle.
 3. Process according to claim 1 wherein the substituted orunsubstituted 1-naphthols have the general formula (I) where R² ishydrogen and R³ is hydrogen and n is zero, one or two and R⁴ are eachindependently halogen, nitro, cyano, C₁-C₈-alkyl, C₁-C₈-haloalkyl orsubstituents of the general formula (II), where, independently, D isabsent and E is a carbonyl group or sulphonyl group and F is R⁶, OR⁶,NH₂, NHR⁶ or NR⁶R⁷ and where R⁶ and R⁷ are each independentlysubstituted or unsubstituted C₁-C₄-alkyl.
 4. Process according to claim1 wherein the substituted or unsubstituted 1-naphthols is 1-naphthol 5.Process according to claim 1 wherein the reactive alkyl compounds is ofthe general formula (IIIa) or (IIIb) represented by R¹—Y  (IIIa), or(R¹—O)₂SO₂   (IIIb) where R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl,C₇-C₁₃-arylalkyl or substituents of the general formula (IV), A-B  (IV)where A is C₂-C₈-alkylene, C₂-C₈-haloalkylene and B is NR⁶R⁷, SR⁶ or OR⁶where R⁶ and R⁷ are each independently substituted or unsubstitutedC₁-C₈-alkyl, C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or NR⁶R⁷together is a 5- to 8-membered heterocycle and Y is chlorine, bromine,iodine or sulphonate.
 6. Process according to claim 1 wherein thereactive alkyl compounds are of the general formula (IIIa) where R¹ is asubstituent of the general formula (IV) where A is C₂-C₄-alkylene orC₂-C₄-haloalkylene and B is NR⁶R⁷or OR⁶ and where R⁶ and R⁷ are eachindependently substituted or unsubstituted C₁-C₄-alkyl or NR⁶R⁷ togetheris a 5- or 6-membered heterocycle and Y is chlorine, bromine, iodine,methanesulphonate, tosylate or trifluoromethanesulphonate.
 7. Processaccording to claim 1 wherein the reactive alkyl compound is2-(N-morpholinyl)ethyl chloride, 2-(N-morpholinyl)ethyl bromide or2-(N-morpholinyl)ethylmethanesulphonate, or ammonium salts thereof. 8.Process according to claim 7 wherein the reactive alkyl compound isN-(2-chloroethyl )morpholine hydrochloride.
 9. Process according toclaim 1 wherein step a) is effected in the presence of a base. 10.Process according claim 9 wherein step a) is effected in the presence ofan aqueous solution of sodium hydroxide having a concentration of from30 to 70% by weight.
 11. Process according to claim 1 wherein step a) iscarried out in ethanol.
 12. Process according to claim 1 wherein step a)is carried out at a temperature of from 0 to 120° C.
 13. Processaccording to claim 1 wherein step b) is carried out in the presence ofpolyphosphoric acid.
 14. Process according to claim 13 wherein the molarratio of polyphosphoric acid to 1-naphthol ether is from 5.0 to 12.0.15. Process according to claim 1 wherein the hydroxylammonium salt ishydroxylamine hydrochloride.
 16. Process according to claim 1 whereinthe carboxylic acid is acetic acid, propionic acid or trifluoroaceticacid.
 17. Process according to claim 1 wherein the reaction temperaturein step b) is from 50 to 130° C.
 18. Process according to claim 1wherein the 4-acylamino-1-naphthol ethers are converted by acidhydrolysis to the ammonium salts of 4-amino-1-naphthol ethers in stepc).
 19. Process according to claim 18 wherein the acid hydrolysis iscarried out in the presence of acids having a pKa of 2 or less in stepc).
 20. Process according to claim 19 wherein the acid hydrolysis iscarried out in the presence of concentrated hydrochloric acid. 21.4-Acylamino-1-naphthol ethers of the general formula (VIIa)

where R¹ is C₃-C₁₂-alkyl, C₂-C₈-haloalkyl, C₇-C₁₃-arylalkyl orsubstituents of the general formula (IV) A-B  (IV) where A isC₂-C₈-alkylene, C₂-C8-haloalkylene and B is NR⁶R⁷, SR⁶ or OR⁶ where R⁶and R⁷ are each independently substituted or unsubstituted C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or NR⁶R⁷ together is a5- to 8-membered heterocycle and R² is hydrogen, halogen or C₁-C₄-alkyland R³ is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy and n is zero,one, two, three or four and R⁴ are each independently halogen, nitro,cyano, protected formyl, C₁-C₈-alkyl, C₇-C₁₀-arylalkyl,C₁-C₈-hydroxyalkyl, C₁-C₈-haloalkyl or C₆-C₁₀-aryl or substituents ofthe general formula (II) D-E-F  (II) where, independently, D is absentor is a C₁-C₈-alkylene radical and E is a carbonyl group or sulphonylgroup and F is R⁶, OR⁶, NH₂, SR⁶, NHR⁶ or NR⁶R⁷ and where R⁶ and R⁷ areeach independently substituted or unsubstituted C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₇-C₁₂-arylalkyl or C₆-C₁₀-aryl or NR⁶R⁷together is a5- to 8-membered heterocycle and R⁵ is C₁-C₆-alkyl or C₁-C₄-haloalkyl.22. 4-(2-([1]-naphthyloxy-[4]-acetamino)ethyl)morpholine. 23.4-(2-([1]-naphthyloxy-[4]-propionylamino)ethyl)morpholine 24.4-(2-([1]-naphthyloxy-[4]-trifluoroacetamino)ethyl)morpholine. 25.Compounds of the general formula (VIIb)

where R⁵ is a C₁-C₆-alkyl or C₁-C₄-haloalkyl radical and An− is theanion of an acid.
 26. Compounds of the general formulae (VIIIa) and(VIIIb),

where R¹, R², R³, R⁴ and n are as defined under formula (VII) and X isthe anion of an acid.
 27. The compound of formula (VIIIa) or (VIIIb)which is 4-(2-([1]-napthyloxy-[4]-amino)ethyl)morpholine dihydrochlorideor the ammonium salt thereof.
 28. A process for preparing pharmaceuticalcompounds comprising providing compounds of the general formulae (VIIIa)and (VIIIb),

where R¹, R², R³, R⁴ and n are as defined under formula (VII) and X isthe anion of an acid.